Benchmarking precision matrix estimation methods for differential co-expression network analysis

Abstract

BackgroundGene expression profiling is widely used to investigate disease mechanisms, but classical approaches such as differential expression or pairwise correlation analyses provide limited interpretability. Network-based differential co-expression methods that model conditional dependencies through partial correlations offer richer insights, yet their application in high-dimensional settings requires estimation of precision matrices. Numerous precision matrix estimation methods (PMEMs) have been proposed, but their relative performance under various conditions remains unclear. ResultsSimulated gene expression datasets with known ground truth correlation structures were used to benchmark a broad set of PMEMs. Performance was strongly affected by data characteristics, including covariance structure, matrix density, covariance values, sample size-to-dimension ratio, and sampling distribution. Among the evaluated methods, GLassoElnetFast consistently showed the highest accuracy in recovering differential edges, although high signal-to-noise ratios and sufficient sample sizes remain essential for reliable inference. ConclusionsEvaluation across diverse simulation conditions demonstrated that no single metric or condition was sufficient to assess PMEM performance. Therefore, previous less extensive evaluations risked misleading conclusions. Our simulation and benchmarking framework supports future method development and ensures reproducible evaluation of newly developed approaches.